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De Frontin Werneck M.B.,Brazilian National Institute of Cancer INCA
Frontiers in Bioscience - Scholar | Year: 2012

It has been recently shown that within heterogeneous tumor masses a small population of less differentiated transformed cells has the ability to self-renew and regenerate the bulk of the tumor. Their similarities with normal stem cells in terms of gene expression patterns, proliferative capacity and surface markers rendered them the name of cancer stem-like cells (CSC), and these are thought to be the tumor initiating cells (TIC). Their limited susceptibility to classical anti-tumor therapy help explain the high incidence of cancer-treatment relapses observed in selected malignancies. Much effort is being directed towards the understanding of factors that maintain CSC survival and their self-renewal capacity, with the goal that these same signaling pathways can be harnessed for treatments that aim at inducing CSC differentiation. This review will discuss the CSC theory, its implications, potential signaling pathways responsible for maintaining their undifferentiated and pluripotent states, and new venues being explored to target these cells in modern cancer therapy. Source


Fazolini N.P.B.,Oswaldo Cruz Institute | Cruz A.L.S.,Brazilian National Institute of Cancer INCA | Werneck M.B.F.,Brazilian National Institute of Cancer INCA | Viol J.P.B.,Oswaldo Cruz Institute | And 2 more authors.
Cell Cycle | Year: 2015

Accumulating evidence suggests that obesity and enhanced inflammatory reactions are predisposing conditions for developing colon cancer. Obesity is associated with high levels of circulating leptin. Leptin is an adipocytokine that is secreted by adipose tissue and modulates immune response and inflammation. Lipid droplets (LD) are organelles involved in lipid metabolism and production of inflammatory mediators, and increased numbers of LD were observed in human colon cancer. Leptin induces the formation of LD in macrophages in a PI3K/mTOR pathway-dependent manner. Moreover, the mTOR is a serine/threonine kinase that plays a key role in cellular growth and is frequently altered in tumors. We therefore investigated the role of leptin in the modulation of mTOR pathway and regulation of lipid metabolism and inflammatory phenotype in intestinal epithelial cells (IEC-6 cells). We show that leptin promotes a dose- and time-dependent enhancement of LD formation. The biogenesis of LD was accompanied by enhanced CXCL1/CINC-1, CCL2/MCP-1 and TGF-β production and increased COX-2 expression in these cells. We demonstrated that leptin-induced increased phosphorylation of STAT3 and AKT and a dose and time-dependent mTORC activation with enhanced phosphorilation of the downstream protein P70S6K protein. Pre-treatment with rapamycin significantly inhibited leptin effects in LD formation, COX-2 and TGF-β production in IEC-6 cells. Moreover, leptin was able to stimulate the proliferation of epithelial cells on a mTOR-dependent manner. We conclude that leptin regulates lipid metabolism, cytokine production and proliferation of intestinal cells through a mechanism largely dependent on activation of the mTOR pathway, thus suggesting that leptin-induced mTOR activation may contribute to the obesity-related enhanced susceptibility to colon carcinoma. © 2015 Taylor & Francis Group, LLC. Source


Milet P.R.,Center Oscar Lambret | Milet P.R.,Brazilian National Institute of Cancer INCA | Mallet Y.,Center Oscar Lambret | El Bedoui S.,Center Oscar Lambret | And 3 more authors.
Oral Oncology | Year: 2010

There are few data focusing on postoperative course after major head and neck cancer surgery in the elderly compared with the younger population. The aim of this study was to assess the impact of age on postoperative outcomes. At hospital admission, we prospectively collected data from 261 patients separated into two groups with regard to their age (those ≥70 years and those <70 years). Twenty-nine of them were over 70 years old. Median length of stay was similar in both populations (22 vs. 21 days, p = 0.66). Incidence of severe postoperative complications was similar: surgical site infection (6/29 vs. 89/232, p = 0.77), pneumonia (4/29 vs. 29/232, p = 0.13) and infection caused by multi-resistant pathogens (1/29 vs. 14/232, p = 0.08). There was no significant increase in postoperative deaths (4/29 vs. 6/232, p = 0.12). The impact of age on postoperative deaths was assessed after adjustment for potential risk factors. In a logistic regression model, postoperative death risk remained insignificantly increased in the elderly (adjusted Odds Ratio = 3.3 [0.7-14.9], p = 0.22). In our experience, the postoperative course in elderly patients is not significantly different from that than in younger patients. © 2009 Elsevier Ltd. All rights reserved. Source


Werneck M.B.F.,Brazilian National Institute of Cancer INCA | Werneck M.B.F.,Oswaldo Cruz Institute | Hottz E.,Oswaldo Cruz Institute | Bozza P.T.,Oswaldo Cruz Institute | Viola J.P.B.,Brazilian National Institute of Cancer INCA
Cell Cycle | Year: 2012

Chronic inflammation is a risk factor for the development of colon cancer, providing genotoxic insults, growth and proangiogenic factors that can promote tumorigenesis and tumor growth. Immunomodulatory agents can interfere with the inflammation that feeds cancer, but their impact on the transformed cell is poorly understood. The calcium/calcineurin signaling pathway, through activation of NFAT, is essential for effective immune responses, and its inhibitors cyclosporin A (CsA) and FK506 are used in the clinics to suppress immunity. Moreover, the kinases GSK3β and mTOR, modulated by PI-3K/Akt, can inhibit NFAT activity, suggesting a cross-talk between the calcium and growth factor signaling pathways. Both NFAT and mTOR activity have been associated with tumorigenesis. We therefore investigated the impact of calcineurin and PI-3K/mTOR inhibition in growth of human colon carcinoma cells. We show that despite the efficient inhibition of NFAT1 activity, FK506 promotes tumor growth, whereas CsA inhibits it due to a delay in cell cycle progression and induction of necroptosis. We found NFκB activation and mTORC1 activity not to be altered by CsA or FK506. Similarly, changes to mitochondrial homeostasis were equivalent upon treatment with these drugs. We further show that, in our model, NFAT1 activation is not modulated by PI3K/mTOR. We conclude that CsA slows cell cycle progression and induces necroptosis of human carcinoma cell lines in a TGFβ-, NFAT-, NFκB- and PI3K/mTOR-independent fashion. Nevertheless, our data suggest that CsA, in addition to its anti-inflammatory capacity, may target transformed colon and esophagus carcinoma cells without affecting non-transformed cells, promoting beneficial tumoristatic effects. © 2012 Landes Bioscience. Source


Werneck M.B.F.,Brazilian National Institute of Cancer INCA | Vieira-De-Abreu A.,Oswaldo Cruz Institute | Chammas R.,University of Sao Paulo | Viola J.P.B.,Brazilian National Institute of Cancer INCA
Cancer Immunology, Immunotherapy | Year: 2011

Members of the nuclear factor of activated T cell (NFAT) family of transcription factors were originally described in T lymphocytes but later shown to be expressed in several immune and non-immune cell types. NFAT proteins can modulate cellular transformation intrinsically, and NFAT-deficient (NFAT1-/-) mice are indeed more susceptible to transformation than wild-type counterparts. However, the contribution of an NFAT1-/- microenvironment to tumor progression has not been studied. We have addressed this question by inoculating NFAT1-/- mice with B16F10 melanoma cells intravenously, an established model of tumor homing and growth. Surprisingly, NFAT1-/- animals sustained less tumor growth in the lungs after melanoma inoculation than wild-type counterparts. Even though melanoma cells equally colonize NFAT1-/- and wild-type lungs, tumors do not progress in the absence of NFAT1 expression. A massive mononuclear perivascular infiltrate and reduced expression of TGF-β in the absence of NFAT1 suggested a role for tumor-infiltrating immune cells and the cytokine milieu. However, these processes are independent of an IL-4-induced regulatory tumor microenvironment, since lack of this cytokine does not alter the phenotype in NFAT1-/- animals. Bone marrow chimera experiments meant to differentiate the contributions of stromal and infiltrating cells to tumor progression demonstrated that NFAT1-induced susceptibility to pulmonary tumor growth depends on NFAT1-expressing parenchyma rather than on bone marrow-derived cells. These results suggest an important role for NFAT1 in radio-resistant tumor-associated parenchyma, which is independent of the anti-tumor immune response and Th1 versus Th2 cytokine milieu established by the cancer cells, but able to promote site-specific tumor growth. © 2011 Springer-Verlag. Source

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